Toxoplasma gondii is a widespread parasite of domestic and wild animals that also commonly infects humans, where it is an important cause of disease in immunocompromised individuals. T. gondii is also a model for many biological features are conserved in other less-easily studied apicomplexan parasites such as Cryptosporidium and Plasmodium (malaria). For example, this group of parasites shares common pathways for protein secretion, motility, and host cell invasion: adaptations that are responsible for the success of these intracellular parasites. The long-term goal of our studies is to elucidate the molecular mechanisms that regulate these conserved pathways in apicomplexan parasites and to define how these adaptations lead to intracellular parasitism. Previous studies have demonstrated the role of actin-based motility in cell invasion, and shown that this process facilitates tissue migration and contributes to pathogenesis. Motility and cell invasion also require calcium-mediated secretion of micronemal proteins, which bind to specific receptors on the host cell or substratum, thus providing traction. The cytoplasmic domains of micronemal proteins link to the motor complex within the parasite, thus bridging substrate attachment with force generation. In the proposed studies, we will define the molecular mechanisms that control three important steps in the function of microneme proteins including, calcium-mediated release, translocation via the motor complex, and proteolytic processing. Importantly, these molecular components and signaling pathways are not found in the host cell, they have been shown to be essential in the parasite using pharmacological and/or genetic analyses, and they are conserved among apicomplexan parasites. Elucidation of the molecular mechanisms that control these events will lead to an increased understanding of unique adaptations that are essential for survival of apicomplexan parasites. They may also lead to improved therapeutic interventions to combat these important pathogens.

Public Health Relevance

Our studies are designed to elucidate the molecular mechanisms that control protein secretion and motility in apicomplexan parasites. The proposed studies will be conducted using T. gondii, which is an important opportunistic pathogen and NIAID category B Biodefense agent. T. gondii is also a laboratory model for other less easily studied parasites such as Plasmodium and Cryptosporidium, which share these same biological pathways. Because these pathways are essential and unique to these parasites, defining their molecular components and regulatory features may enable future development of new treatments for parasitic diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-M (02))
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Mcgugan, Glen C
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Washington University
Schools of Medicine
Saint Louis
United States
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Long, Shaojun; Brown, Kevin M; Sibley, L David (2018) CRISPR-mediated Tagging with BirA Allows Proximity Labeling in Toxoplasma gondii. Bio Protoc 8:
Brown, Kevin M; Sibley, L David (2018) Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase. Cell Host Microbe 24:804-816.e6
Brown, Kevin M; Long, Shaojun; Sibley, L David (2018) Conditional Knockdown of Proteins Using Auxin-inducible Degron (AID) Fusions in Toxoplasma gondii. Bio Protoc 8:
Shen, Bang; Brown, Kevin; Long, Shaojun et al. (2017) Development of CRISPR/Cas9 for Efficient Genome Editing in Toxoplasma gondii. Methods Mol Biol 1498:79-103
Jones, Nathaniel G; Wang, Qiuling; Sibley, L David (2017) Secreted protein kinases regulate cyst burden during chronic toxoplasmosis. Cell Microbiol 19:
Long, Shaojun; Anthony, Bryan; Drewry, Lisa L et al. (2017) A conserved ankyrin repeat-containing protein regulates conoid stability, motility and cell invasion in Toxoplasma gondii. Nat Commun 8:2236
Garcia, Celia R S; Alves, Eduardo; Pereira, Pedro H S et al. (2017) InsP3 Signaling in Apicomplexan Parasites. Curr Top Med Chem 17:2158-2165
Long, Shaojun; Brown, Kevin M; Drewry, Lisa L et al. (2017) Calmodulin-like proteins localized to the conoid regulate motility and cell invasion by Toxoplasma gondii. PLoS Pathog 13:e1006379
Rutaganira, Florentine U; Barks, Jennifer; Dhason, Mary Savari et al. (2017) Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii. J Med Chem 60:9976-9989
Brown, Kevin M; Long, Shaojun; Sibley, L David (2017) Plasma Membrane Association by N-Acylation Governs PKG Function in Toxoplasma gondii. MBio 8:

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